Effective immunity is dependent on long-surviving memory T cells. Various memory subsets make distinct contributions to immune protection, especially in peripheral infection. It has been suggested that T cells in nonlymphoid tissues are important during local infection, although their relationship with populations in the circulation remains poorly defined. Here we describe a unique memory T cell subset present after acute infection with herpes simplex virus that remained resident in the skin and in latently infected sensory ganglia. These T cells were in disequilibrium with the circulating lymphocyte pool and controlled new infection with this virus. Thus, these cells represent an example of tissue-resident memory T cells that can provide protective immunity at points of pathogen entry.

Skin-derived dendritic cells (DCs) include Langerhans cells, classical dermal DCs and a langerin-positive CD103(+) dermal subset. We examined their involvement in the presentation of skin-associated viral and self antigens. Only the CD103(+) subset efficiently presented antigens of herpes simplex virus type 1 to naive CD8(+) T cells, although all subsets presented these antigens to CD4(+) T cells. This showed that CD103(+) DCs were the migratory subset most efficient at processing viral antigens into the major histocompatibility complex class I pathway, potentially through cross-presentation. This was supported by data showing only CD103(+) DCs efficiently cross-presented skin-derived self antigens. This indicates CD103(+) DCs are the main migratory subtype able to cross-present viral and self antigens, which identifies another level of specialization for skin DCs.

The brain is not routinely surveyed by lymphocytes and is defined as an immuno-privileged site. However, viral infection of the brain results in the infiltration and long-term persistence of pathogenspecific CD8 + T cells. These cells survive without replenishment from the circulation and are referred to as resident memory T cells (Trm). Brain Trm selectively express the integrin CD103, the expression of which is dependent on antigen recognition within the tissue. After clearance of virus, CD8 + T cells persist in tight clusters, presumably at prior infection hot spots. Antigen persistence is not a prerequisite for T-cell retention, as suggested by the failure to detect viral genomes in the T-cell clusters. Furthermore, we show that an intracranial dendritic cell immunization regimen, which allows the transient introduction of antigen, also results in the generation of memory T cells that persist long term in the brain. Brain Trm die rapidly on isolation from the tissue and fail to undergo recall expansion after adoptive transfer into the bloodstream of antigen-challenged recipients. These ex vivo defects imply a dependency on the local milieu for function and survival. Cumulatively, this work shows that Trm are a specialized population of memory T cells that can be deposited in tissues previously thought to be beyond routine immune surveillance.

The classical paradigm for dendritic cell function derives from the study of Langerhans cells, which predominate within skin epidermis. After an encounter with foreign agents, Langerhans cells are thought to migrate to draining lymph nodes, where they initiate T cell priming. Contrary to this, we show here that infection of murine epidermis by herpes simplex virus did not result in the priming of virus-specific cytotoxic T lymphocytes by Langerhans cells. Rather, the priming response required a distinct CD8alpha+ dendritic cell subset. Thus, the traditional view of Langerhans cells in epidermal immunity needs to be revisited to accommodate a requirement for other dendritic cells in this response.